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Blockade of nitrergic neuroeffector transmission in guinea-pig colon by a selective inhibitor of soluble guanylyl cyclase

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Abstract:

The role of soluble guanylyl cyclase in nitrergic inhibitory neuroeffector transmission was investigated in the longitudinal muscle from guinea-pig colon, by using an inhibitor of soluble guanylyl cyclase, 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ). In preparations precontracted with histamine, electrical field stimulation (EFS) or exogenous nitric oxide (NO) induced relaxations. The relaxation induced by NO-application was abolished by ODQ. Both ODQ and the NO-synthase inhibitor N ω-nitro-L-arginine (L-NOARG) partially inhibited the EFS-evoked relaxation to a similar extent. These effects were dose-dependent. The inhibition was more pronounced in the late phase of the EFS-induced relaxation. The inhibitory effect of ODQ on EFS-induced relaxation was not affected by additional application ofL-NOARG. When NO-formation was blocked byL-NOARG, a subsequent addition of ODQ gave no further inhibition of the relaxation. These findings suggest that inhibitory non-adrenergic, non-cholinergic neurotransmission in guinea-pig colon is dependent on endogenous formation of NO, and that the NO-effect is exclusively mediated via the soluble guanylyl cyclase pathway. The existence of an NO-independent inhibitory transmission, which is not mediated through the cyclic GMP pathway, is also indicated. Furthermore, it is demonstrated that the NO/soluble guanylyl cyclase-independent transmission has an earlier onset as compared with the NO/soluble guanylyl cyclase-dependent pathway.

Keywords: ODQ; autonomic neurotransmission; nitric oxide; smooth muscle relaxation; soluble guanylyl cyclase

Document Type: Original Article

DOI: http://dx.doi.org/10.1046/j.1365-201X.1998.0274f.x

Affiliations: Department of Physiology and Pharmacology, Karolinska Institute, Stockholm

Publication date: January 1, 1998

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